Heart failure (HF) is one of the largest contributors to disease burden in the United States with an annual incidence of 550,000 cases and mortality of 42% within 5 years after diagnosis. An improved understanding of left ventricular (LV) remodeling that comprises the substrate for progression of HF is critical for the delineation of novel pathways and therapeutic targets, and for the identification of biomarkers to predict and track LV remodeling to allow for the initiation of early and effective therapy in patients at risk or worsening HF. This is an area of unmet clinical need because our current understanding of remodeling is incomplete, and risk- stratification strategies lack adequate specificity and sensitivity. MicroRNAs (miRNA) and other non-coding RNAs have been implicated in human heart disease, and their recent discovery in plasma has led to the hypothesis that extracellular RNAs may mediate disease-specific signaling, and spurred their development as biomarkers and disease reporters. Based on the initial findings of our and other laboratories that extracellular RNAs can both predict and play an important role in LV remodeling in HF patients, the objective of this proposal is firstly, to delineate the role of newly discovered as well as previously reported extracellular RNAs (ex-RNAs) in mediating LV remodeling. Secondly, we aim to characterize these ex-RNAs as prognostic biomarkers in HF patients that can be easily imported into the clinic to identify at-risk patients. The group of investigators in this proposal, spanning multiple disciplines within cardiovascular and ex-RNA research will test the central hypothesis that (1) ex-RNAs can predict LV remodeling (a surrogate endpoint) as well as clinical outcomes in patients with HF; (2) ex-RNAs can function not only as disease reporters, but also as mediators of LV remodeling in animal models; and (3) these ex-RNAs can be therapeutic targets in validated animal models of heart disease. The findings resulting from this proposal would identify novel pathways and therapeutic targets in HF, and lay the platform for more effective and targeted HF treatment based on prognostic biomarkers and disease reporters.